Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• This invention is in the field of pharmaceutical agents exhibiting central nervous system (CNS) activities. More specifically, the invention relates to novel indole derivatives, to a process for their preparation, to pharmaceutical compositions comprising the compounds, and to methods of treating therewith.
• novel indole derivatives are potentially suitable for counteracting (including preventing, relieving and curing) certain CNS disorders.
• 5-HT serotonin
• the ligand 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) binds with high affinity to 5-HT 1A receptors, while another ligand, a 2,4(1H,3H)-quinazolinedione derivative (adopted name: ketanserin) exhibits high affinity for the 5-HT2 receptor subtype. It is worth noting that none of these synthetic ligands have any chemical resemblance whatsoever to the physiological binding partner, i.e. 5-HT. For a recent review of 5-HT receptor- ligand interactions reference is made to J.R. Fozard: Trends in Pharmacol.Sci. 8W (1987), 501-506.
• indole derivatives which are chemically closer related to 5-HT, such as RU 24969, which is a 3-(tetrahydropyridin-4-yl)-indole (Ann.Reports Med.Chem. 21 (1986), 42-43) have high affinity for 5-HT1 recognition sites, but generally they show only limited capacity to discriminate between the 5-HT 1A and 5-HT 1B receptor subtypes.
• N-(phthalimidoalkyl) derivatives having affinity to 5-HT 1A receptors.
• One of these compounds is a derivative of an indolylalkylamine, having the formula wherein R' is hydrogen and R is N-(4-phthalimidobutyl), which is structurally related to the compounds of the invention.
• the compounds exhibits a considerably higher IC50-value for 5-HT 1A receptor binding than the compounds according to the invention.
• EP,A,0236930 discloses aromatic 2-aminoalkyl-1,2,benzoisothiazol-3(2H)one-1,1-dioxide derivatives having anxiolytic and antihypertensive properties.
• One of these compounds which is structurally closely related to the compounds of the invention is a derivative of an indolylalkylamine having the formula 2-[4-[(5-methoxy-indol-3-yl)ethylamino]butyl]-1,2-benzoisothiazol-3-(2H)one-1,1-dioxide.
• R1, R2, R3 and R4 which may be the same or different, each is selected from the group consisting of hydrogen; lower alkyl containing from 1 to 4 carbon atoms, in which one or more hydrogen atoms may be substituted by halogen, e.g. CF3; OR7 in which R7 is hydrogen or C1 ⁇ 4-alkyl; halogen, e.g.
• A1 represents a straight or branched alkylene chain containing from 2 to 4 carbon atoms
• A2 is a straight or branched saturated or unsaturated hydrocarbon chain containing from 2 to 6 carbon atoms
• the compounds of formula I may be converted into any physiological acceptable salts thereof.
• the invention includes within its scope all optical isomers of compounds of the general formula (I) and their mixtures including racemic mixtures thereof.
• Rat brain tissue (as specified in the table hereinafter) was homogenized using a Polytron homogenizer. The final pellet was resuspended in 125 vol (tissue wet weight) of buffer.
• Labelling of the 5-HT 1B receptor was complicated by the fact that the available ligand 3H-5-HT is nonselective. However, by inclusion of the 5-HT 1A selective agent 8-OH-DPAT in the assay, labelling of the 5-HT 1A receptor could be avoided and a relatively selective labelling of the 5-HT 1B receptor could be accomplished.
• Receptor binding IC50 Compound 5-HT 1A 5-HT 1B Buspirone 20 above 1000 Gepirone 248 above 1000 Ipsapirone 25 above 1000 8-OH-DPAT 3,4 above 1000 2-[4-[(5-methoxy-indol-3-yl) ethylamino]-butyl]-1,2-benzoisothiazol-3(2H)one-1,1-dioxide 76 2571
• Example 1 26 480
• the present invention also provides a process for preparing the compounds of the general formula (I) and physiologically acceptable salts thereof, which process is outlined hereinafter.
• the reaction may conveniently be effected in an organic solvent, such as an aprotic solvent, e.g. acetonitrile or dimethylformamide in the presence of a base, for ex-ample potassium carbonate.
• an organic solvent such as an aprotic solvent, e.g. acetonitrile or dimethylformamide
• the reaction can be conducted in the presence of a salt of hydrogen iodide, e.g. potassium iodide.
• the reaction is completed with stirring at a temperature above ambient.
• the reaction product obtained following, if necessary, after the conversion of Z into hydrogen may be recovered by conventional means and, if desirable, subjected to purification, e.g. by suitable chromatographic procedures.
• the purified reaction product may be converted into a physiologically acceptable salt.
• salts include acid addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, nitrates, oxalates, phosphates, tartrates, citrates, fumarates, maleates, succinates, and sulphonates e.g. mesylates.
• selected salts may be subjected to further purification by recrystallization.
• the compound of the invention together with a conventional adjuvant, carrier, or diluent, and if desired in the form of a Pharmaceutically-acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
• Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed.
• Tablets containing one (1) milligram of active ingredient or, more broadly, one (1) to thirty (30) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
• the compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g., for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
• Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
• Such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
• the pharmaceutical preparations can be sterilized and mixed, if desired, with auxilliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compound.
• auxilliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compound.
• injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
• Ampoules are convenient unit dosage forms.
• tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
• a syrup, elixir or like can be used when a sweetened vehicle can be employed.
• the compound of the invention is dispensed in unit dosages form comprising 0.05-100 mg in a pharmaceutically-acceptable carrier per unit dosage.
• a typical tablet which may be prepared by conventional tabletting techniques contains: Active compound 1.0 mg Lactosum 67.8 mg Ph.Eur. Avicel 31.4 mg Amberlite IRP 88 1.0 mg Magnesii stearas 0.25 mg Ph.Eur.
• the compounds of the invention are extremely useful in the treatment of central nervous system ailments or disorders, when administered in an amount effective for the alleviation, amelioration, or elimination thereof.
• the compounds of the invention may accordingly be administered to a subject, e.g., a living animal body, including a human, in need of the same for the treatment, alleviation, amelioration, or elimination of an indication, associated with the central nervous system and the 5-HT receptors, which requires such psychopharmaceutical treatment, if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulfate, in any event prepared in the usual or conventional manner, e.g., evaporation to dryness of the free base in solution together with the acid), ordinarily concurrently, simultaneously, or together with a pharmaceutically-acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective psychopharmaceutical central nervous system ailment alleviating amount, and in any event an amount which is effective for the alleviation of such a central nervous system ailment due to their 5-
• Suitable dosage ranges are 1-200 milligrams daily, 1-100 milligrams daily, and especially 1-30 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Indole Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Luminescent Compositions (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Saccharide Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 1990
  • 1990-02-13 DK DK037790A patent/DK37790A/da not_active Application Discontinuation
• 1991
  • 1991-01-23 US US07/645,381 patent/US5126363A/en not_active Expired - Fee Related
  • 1991-01-25 IE IE26091A patent/IE69761B1/en not_active IP Right Cessation
  • 1991-01-31 IL IL9710591A patent/IL97105A/en not_active IP Right Cessation
  • 1991-02-06 ZA ZA91886A patent/ZA91886B/xx unknown
  • 1991-02-11 NZ NZ237066A patent/NZ237066A/xx unknown
  • 1991-02-13 DK DK91904005.5T patent/DK0515462T3/da active
  • 1991-02-13 CA CA002074727A patent/CA2074727A1/en not_active Abandoned
  • 1991-02-13 WO PCT/DK1991/000041 patent/WO1991012252A1/en active IP Right Grant
  • 1991-02-13 AT AT91904005T patent/ATE123283T1/de active
  • 1991-02-13 PT PT96757A patent/PT96757B/pt not_active IP Right Cessation
  • 1991-02-13 JP JP3504066A patent/JPH05503525A/ja active Pending
  • 1991-02-13 DE DE69110124T patent/DE69110124T2/de not_active Expired - Fee Related
  • 1991-02-13 EP EP91904005A patent/EP0515462B1/en not_active Expired - Lifetime
  • 1991-02-13 AU AU73265/91A patent/AU641482B2/en not_active Ceased
• 1992
  • 1992-08-03 FI FI923492A patent/FI923492A0/fi not_active Application Discontinuation
  • 1992-08-12 NO NO923153A patent/NO923153D0/no unknown

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